Breast cancer is the most commonly diagnosed cancer in women worldwide with about 1.38 million newly diagnosed cases each year. Nearly 70% of breast cancer patients are hormone-receptor positive. For these patients, tamoxifen has been the most widely used adjuvant endocrine therapy. While tamoxifen is effective, it is a pro-drug that requires extensive CYP2D6 metabolism into active metabolites such as endoxifen (ENX) (FIG. 1). Recently, it has been reported that genetic polymorphism in CYP2D6 can impair the biotransformation of tamoxifen into its active metabolites. To overcome the poor outcomes associated with breast cancer therapy for patients with reduced CYP2D6 activity, direct administration of endoxifen has been advocated. Clinical trials are currently being conducted on the oral use of endoxifen as the hydrochloride salt form.
Apart from the oral route, transdermal drug delivery of the endoxifen has also been explored. However, studies have shown a limited drug flux through skin. Based on the required daily dose of endoxifen, therapeutically relevant concentrations of endoxifen have not been achieved via transdermal drug delivery. Therefore, further studies are needed for the effective delivery of endoxifen through skin. Moreover, a transdermal gel of 4-hydroxy metabolite of tamoxifen is currently under phase 2 clinical trials, indicating the potential for transdermal administration of active metabolites like endoxifen in the management of breast cancer.
The delivery of drugs and/or cosmetics through skin is an alternative route to painful injections. The transdermal delivery market was valued at about $21.5 billion in 2010 and is predicted to reach about $31.5 billion by 2015. The annual U.S. market for transdermal patches is estimated to be more than about $3 billion. Transdermal drugs account for more than about 12% of the global drug delivery market.
Conventionally, a variety of transdermal diffusion cells have been developed for the evaluation or testing of in vitro permeation characteristics of transdermally delivered drugs. In principle, some of the transdermal diffusion cells developed are based on the static, non flowing cells in which the donor and receptor compartments can be placed either vertically (Franz type) or horizontally (side-by-side). Some of the transdermal diffusion cells developed are in-line, flow through cells that offer the advantage of continual replenishment of receptor fluid and hence aid in maintaining a condition similar to microcirculation in the in vivo setting.
Several modified versions of these diffusion cells have also been fabricated and validated against the conventional apparatuses. For example, the permeation characteristics of hydrocortisone were compared using the “enhancer cell”, which is a modified version of a USP type II dissolution apparatus serving as a diffusion cell. Modified automatic sampling apparatuses have also been developed. These static and flow-through cells have been compared and validated.
However, a major drawback of the above mentioned cells and known commercial cells such as the ILC14 Automated System from PermeGear Inc., the SYSTEM 912-24 from Logan Instruments Corp, and Vertical/horizontal diffusion cells from Shanghai Kaikai Science and Technology Trade Ltd. is the requirement of relatively large amounts of the drug(s) to be tested and relatively large areas and/or amounts of membrane (e.g, skin). Typically, this major drawback is largely due to the inherent design of the cells and systems.
Endoxifen's physicochemical properties make it a good candidate for transdermal delivery. However, as an investigative drug, its limited supply and high cost make it difficult to conduct extensive pre-formulation studies.
Similarly, other investigational new drug entities are also available in limited supply and are also prohibitively expensive. This makes it difficult to conduct extensive pre-formulation studies, particularly those requiring large amounts of the drugs, such as, in vitro permeation studies through the skin to evaluate the transdermal drug delivery potential of a drug candidate. With the economic environment in pharmaceutical firms becoming more tenuous and pharmaceutical cost containment becoming a main focus, the need to develop pre-formulation testing systems that utilize minimum amounts of the drugs to be tested is the need of the hour. As mentioned above, a major drawback of current known cells/systems due to their inherent design is the requirement of relatively large amounts of the drug to be tested and relatively large areas/amount of membranes (e.g., skin).
Thus, there is a need to provide a diffusion cell and/or diffusion cell system that avoids or at least ameliorates one or more of the disadvantages described above.